Directly compressible composition comprising microcrystalline cellulose

ABSTRACT

The present invention relates to a directly compressible composition for the production of tablets which comprise fine-grained polyvinyl alcohols (PVAs) and fine-grained microcrystalline celluloses (MCCs) in a co-mixture. The present invention also relates to the use of this mixture and to a process for the preparation thereof.

The present invention relates to a directly compressible composition forthe production of tablets which comprise fine-grained polyvinyl alcohols(PVAs) and fine-grained microcrystalline celluloses (MCCs) in aco-mixture. The present invention also relates to the use of thismixture and to a process for the preparation thereof.

PRIOR ART

Polyvinyl alcohols (PVAs) are synthetic polymers which are available invarious grades, in particular with respect to degree of polymerisationand their viscosity. Polyvinyl alcohols are obtained by alkalinehydrolysis of polyvinyl acetate. Polyvinyl acetate is in turn obtainedby free-radical polymerisation from vinyl acetate. Through differentchain lengths and different degrees of hydrolysis of the polyvinylacetates employed, polyvinyl alcohols (PVAs) having a very wide varietyof physical properties can be obtained. Polyvinyl alcohols are employed,in particular, as film formers, adhesive gels and as viscositymodulator, in a multiplicity of areas of application, for examplepaints, papers, textiles, cosmetics and in pharmaceuticals, includingdrug delivery systems, etc.

In the pharmaceutical industry, the use of PVAs is particularlyinteresting in pharmaceutical preparations, such as, for example, inophthalmic preparations, as film formers for coated tablets, as bindersin granules or as coating component in plasters, and also in drugdelivery systems. Of very particular interest is the use of various PVAgrades in the formulation of solid oral pharmaceutical administrationforms having extended release of active compound, for example inso-called “retard tablets”. In these tablets, the active compound is infinely divided form in a PVA matrix.

After taking orally, delayed release of active compound frompolymer-containing pharmaceutical formulations of this type is achievedthrough the tablets not dissolving directly in the presence of liquid,such as in the mouth or gastrointestinal tract, but instead swelling anda gel forms from which the active compound is only released little bylittle by diffusion and slow erosion of the gel matrix in thegastrointestinal tract. This delayed release of active compound from theretard tablets in turn results in an approximately constant level ofactive compound in the blood and thus in an improved therapeutic effect.

This means that galenically modified tablets of this type enable theactive compound to be released from the administration form in acontrolled manner over an extended time in the body, in order thus tomaintain a therapeutically effective blood level of the medicament overan extended period (several hours).

The two essential advantages of such retarded formulations are—incontrast to tablets having immediate release of active compound aftertaking—firstly the avoidance of undesired, possibly also toxicblood/plasma levels of the API (API: active pharmaceutical ingredient)and also a reduction in the frequency with which the tablets are taken(for example only once/daily instead of three times/daily) and thus animprovement in so-called patient compliance, which is in turn associatedwith an improved therapeutic outcome of the medicinal treatment.

Known polyvinyl alcohols which are specified for use in pharmaceuticalformulations according to the various pharmacopoeias (PharmacopoeaEuropaea, Ph. Eur.; United States Pharmacopoeia (USP), and the JapanesePharmacopoeia (JP or JPE), but cannot be tableted directly by the actionof pressure or only under particular conditions.

A particular problem in this connection thus consists in the productionin a simple manner of tablets which principally consist of correspondingPVAs as active compound excipient in which the active compound ishomogeneously distributed. Direct tabletability of PVA-containingformulations can usually only be achieved in the presence of relativelyhigh proportions of further binders, such as lactose, and of lubricantsand possibly further additives. Formulations in which PVAs are employedas active compound excipient are frequently prepared in the presence ofaqueous or alcoholic solutions. For example, it is known to producecorresponding tablets having extended release of active compound bycompressing the active compound and PVA in the presence of furtheradditives after wet granulation. The latter is associated with thedisadvantage that the solvents necessary for wet granulation have to beremoved again with high input of energy.

OBJECT OF THE PRESENT INVENTION

As can be seen from the description above, swelling polymers, from whichthe active compound is released in a time-controlled manner viadiffusion and erosion processes after moistening, for example, in thestomach and intestine and made available for resorption, are frequentlyemployed in order to achieve the desired retardation effects.

Polyvinyl alcohols (PVAs) are usually used if, for example,incompatibility reactions exist between active compound and thehydroxypropylmethyl-celluloses (HPMCs) frequently used as retardationpolymer or if the HPMC grades employed exhibit an unsatisfactory releaseprofile of the active compound.

For rapid tablet development with retardation effect, the pharmaceuticalformulation scientist requires a swelling polymer which is directlycompressible and nevertheless releases the active compound in atime-controlled manner. However, known pulverulent PVAs are per se notdirectly compressible and give tablets of unsatisfactory hardness whichcannot be handled in pharmaceutical practice, since, for example, theyhave an undesired tendency to break or have excessively high abrasion.

For rapid development of such retard tablets based on polyvinylalcohols, directly compressible polyvinyl alcohol excipient materialsare therefore desirable. Excipient materials of this type would makeinconvenient and expensive granulation steps, which are usuallynecessary in order to make the tableting mixtures compressible,superfluous.

The object of the present invention is therefore to provide directlycompressible retardation matrices which make time-consuming granulationprocesses superfluous; i.e. steps which consist of moistening withgranulation liquids, mechanical mixing in mixing systems or influidised-bed equipment, and post-drying processes for the removal ofthe granulation liquids and sieving, so that time and energy can besaved, but also expensive and time-consuming investment in specialgranulation equipment. The object of the present invention is also toprovide advantageous directly compressible retardation matrices of thistype based on compositions consisting predominantly of PVAs. Inaddition, it is an object of the present invention to provide a processby means of which PVAs, or commercially available PVA grades, can beconverted into a directly compressible state.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to directly compressible co-mixtures whichcomprise fine-grained polyvinyl alcohols (PVAs) and fine-grainedmicro-crystalline celluloses (MCCs) and by means of which thepharmaceutical formulation scientist is provided with directlycompressible compositions having retarded release of active compound.The present invention preferably relates to mixtures in which thefine-grained polyvinyl alcohols (PVAs) and fine-grained microcrystallinecelluloses (MCCs) employed meet the requirements of the pharmacopoeias(Ph. Eur., USP/NF and JPE. The object of the present invention isachieved, in particular, by directly compressible co-mixtures,comprising fine-grained microcrystalline celluloses having averageparticle sizes of D_(v50)<100 μm, preferably having average particlesizes of D_(v50)<65 μm, particularly preferably having average particlesizes D_(v50)<20 μm, in particular in the range of D_(v50) 1 μm-20 μm.

Directly compressible co-mixtures according to the invention havingimproved properties comprise the fine-grained polyvinyl alcohols andfine-grained microcrystalline celluloses described in a ratio of 5:1 to1:5, based on the weight, preferably in a ratio in the range from 2:1 to1:2, especially preferably in a ratio in the region of 1:1.

In accordance with the invention, corresponding directly compressiblecompositions may comprise fine-grained polyvinyl alcohols (PVAs) ofgrades 18-88, 26-88 and 40-88 which conform to the pharmacopoeias Ph.Eur., JPE and USP and all grades in between, and grade 28-99, whichconforms to JPE and Ph. Eur.

The object of the present invention is achieved, in particular, bydirectly compressible co-mixtures, comprising fine-grained polyvinylalcohols (PVAs) which conform to Ph. Eur. and which have been obtainedby polymerisation of vinyl acetate and by subsequent partial orvirtually complete hydrolysis of the polyvinyl acetate. Particularlysuitable fine-grained PVAs of this type of those which have an averagerelative molecular weight and range between 20,000 and 150,000 g/mol,and which have a viscosity, according to Ph. Eur., In the range 3-70mPa·s, (measured in a 4% solution at 20° C.) and have an ester value ofnot greater than 280 mg KOH/g (degree of hydrolysis >72.2 mol %).

Especially suitable are corresponding directly compressible co-mixtureswhich comprise polyvinyl alcohols (PVAs) which are water-swellableresins which, according to USP, are characterised by the formula

(C₂H₄O)_(n)

in which

n denotes an integer in the range from 500 and up to 5,000, and whichhave been obtained by 85-89% hydrolysis of the polyvinyl acetate.

In addition, the present invention also relates to activecompound-containing tablets having extended release of active compoundover several hours, more precisely tablets comprising a co-mixture offine-grained polyvinyl alcohols (PVAs) and fine-grained microcrystallinecelluloses (MCCs), as characterised above.

In addition, it has been found that active compound-containing tabletswhich comprise a corresponding directly compressible co-mixture in anamount of 1-99% by weight, preferably in an amount of 5-95% by weight,very particularly preferably in an amount of 10-90% by weight, based onthe total weight of the tablet, have the desired, extended release ofactive compound.

Tablets having particularly high tablet hardnesses which requiresurprisingly low ejection forces in the production process, and whichhave only low friabilities of ≤0.2% by weight, can advantageously beobtained with such compositions, even on use of low pressing forces.

Even on use of co-mixtures according to the invention by the action of apressing force of 10 kN, tablets having a tablet hardness of ≥153 kN areobtained with a friability of ≤0.2% by weight. By compression with apressing force of 20 kN, use of the co-mixtures according to theinvention gives tablets having hardnesses of ≥289N which havefriabilities of ≤0.1% by weight.

Tablets having delayed release of active compound which preferablycomprise active compounds from BCS class I, either alone or incombination with other active compounds, can be produced particularlywell using the co-mixtures described. If desired and if there is aclinical necessity, however, active compounds from other BCS classes canalso be converted into directly compressible administration forms havingretarded release of active compound by means of the process according tothe invention.

DETAILED DESCRIPTION OF THE INVENTION

Adequate efficacy of medicaments frequently depends on uniform dosingand requires multiple administration per day so that undesired sideeffects can be avoided. However, this is not desirable with respect topatient compliance. For the administration of certain active compounds,it is therefore desirable to be able to provide tablet formulations bymeans of which release of active compound proceeds slowly over hours, sothat, when taken regularly, a substantially constant effective bloodlevel becomes established over the day, but it is only necessary to takeonce per day.

The demands made of the respective composition vary depending on theactive compounds to be employed. Depending on their chemical andphysical properties, other active compound excipients and tableting aidshave to be used, since not every active compound is compatible withevery tableting aid or cannot be processed with one another owing to thechemical and physical properties.

The bioavailability of active compounds can be classified in accordancewith a Biopharmaceutics Classification System (BCS), which was developedby Gordon Amidon in the USA in the mid-1990s and has now become part ofboth a US FDA (Food And Drug Administration) guideline and also aEuropean Medicines Agency guideline for assessment of the bioequivalenceof medicaments.

For example, active compounds in BCS class I are active compounds havinghigh solubility and high permeability. Their resorption is controlledonly by the speed of stomach and intestine emptying. In the case ofactive compounds which belong to this class, but whose efficacy isdesired over the entire day, attempts are being made to developformulations which enable delayed, uniform release of active compound.

The Biopharmaceutics Classification System (BCS for short) describescorrelations which play an important role in the oral administration ofdrugs. The system is based on the paper by G. Amidon and colleagues from1995. In this paper, the authors describe that the oral bioavailabilityof drugs is influenced principally by their solubility, the dissolutionrate and the permeability through biological membranes (Amidon G L,Lennernas H, Shah V P, Crison J R. A theoretical basis for abiopharmaceutic drug classification: the correlation of in vitro productdissolution and in vivo bioavailability. Pharm Res. 1995; 12:413.)

In the case of active compounds in BCS class 1, both the solubility andthe permeability are high.

This means that, if both the solubility and also the permeability of thedrug are high, it can be assumed that the absorption rate is determinedprincipally by the rate of stomach and intestine emptying.

Since August 2000, the BCS system has been used in the approval processfor proprietary medicinal products of the American approval authorityfor medicines, the FDA (Food And Drug Administration). Under certainprerequisites, bioavailability and bioequivalence studies can be waivedin the application for approval of proprietary medicinal products if itis demonstrated using the BCS system that the new proprietary medicinalproduct (PMP) and a PMP which has already been approved for the samedrug must be bioequivalent. An application can then be made for a waiverof the obligation to carry out these expensive and in this caseunnecessary bioavailability studies. To this end, the drug in therespective medicinal form must meet certain requirements with respect tothe principal parameters solubility, permeability and dissolution rate.

Solubility

The highest dose of the drug must dissolve completely in a maximum of250 ml of an aqueous dissolution medium in a pH range between pH 1 andpH 7.5.

Permeability

A drug has high permeability if at least 90% of an administered dose isabsorbed by the body. This must be demonstrated by suitable data (forexample mass balance studies).

Dissolution Rate

The medicinal form must ensure rapid release of the drug. This must bedemonstrated by suitable in vitro release tests (either rotating basketor rotating paddle method). At least 85% of the corresponding dose mustbe released within 30 minutes in three different release media (0.1 NHCL, pH 4.5 buffer and pH 6.8 buffer).

As described above, the aim of the invention is to make a highly solubleactive compound available uniformly over hours. The solution to thisproblem has surprisingly been made possible by the use of polymericactive compound excipients, where the latter slowly form a gel in thepresence of physiological fluids, such as saliva or gastric orintestinal juice, and release the active compound from the tablet matrixslowly and in a controlled manner by diffusion.

A solution is provided here by polyvinyl alcohols (PVAs), which, assynthetic polymers, are water-soluble resins and have excellentfilm-forming and emulsifying properties and form a gel in aqueoussolutions. According to USP, PVAs are characterised by the formula

(C₂H₄O)_(n)

in which

n denotes an integer in the range from 500 to 5,000. Depending on themolecular size of these polymers and their chemical composition, theirproperties vary greatly, in particular with respect to the watersolubility, but also in relation to the tabletability.

PVAs are prepared from polyvinyl acetate, with some or all of thefunctional acetate groups being hydrolysed in order to obtain functionalalcohol groups. The solubility of the polymer in aqueous media increaseswith the degree of hydrolysis, but the crystallinity and melting pointof the polymer also increase. In addition, the glass transitiontemperature varies depending on the degree of hydrolysis.

For example, a 38% hydrolysed material does not have a melting point,but has a glass transition temperature of about 48° C., whereas a 75%hydrolysed material has a melting point of about 178° C., an 88%hydrolysed material has a melting point of about 196° C. and a 99%hydrolysed material has a melting point of about 220° C., but thepolymer tends to decompose rapidly at a temperature above 200° C.

For the preparation of the compositions according to the invention, usecan be made of polyvinyl alcohols (PVAs) of grades 18-88, 26-88 and40-88 and all grades in between, including grade 28-99 in accordancewith JPE and Ph. Eur.

Although polyvinyl alcohols are soluble in water, they are virtuallyinsoluble in almost all organic solvents, with the exception of a fewsolvents, such as, for example, in ethanol with low solubility. Theseproperties of the polymers make it very difficult to prepare tabletformulations which comprise a high proportion of PVAs and which aredirectly tabletable.

For use in pharmaceutical formulations, polyvinyl alcohols of differentdegrees of hydrolysis are specified in the various pharmacopoeia.

The European Pharmacopoeia prescribes that a permissible polyvinylalcohol for use in pharmaceutical doses must have an ester value of notgreater than 280 and an average relative molecular weight between 20,000and 150,000. The percentage of hydrolysis (H) can be calculated from thefollowing equation:

H=((100−(0.1535)(EV))/(100−(0.0749)(EV)))×100,

where EV corresponds to the ester value of the polymer. The ester valuemeans the quantity of potassium hydroxide in mg required to saponify theesters in 1 g of sample. The ester value is calculated from thedifference between the saponification value and the acid value.

Thus, according to the monograph in the European Pharmacopoeia, only PVApolymers having a percentage hydrolysis of greater than 72.2% can beemployed.

According to the United States Pharmacopeia, polyvinyl alcohols whichare suitable for use in pharmaceutical administration forms must have apercentage degree of hydrolysis of between 85 and 89% and a degree ofpolymerisation of 500 to 5,000. The degree of polymerisation (DM) iscalculated by the equation:

DM=(molar mass)/((86)−(0.42(the degree of hydrolysis)))

A PVA which can be employed in pharmaceutical formulations in accordancewith the European Pharmacopoeia monograph is a PVA having a degree ofhydrolysis of between 72.2% and 90%, which covers both PVAs inaccordance with the Ph. Eur. (hydrolysis of more than 72.2%, but lessthan 90%, and also those in accordance with the USP (degree ofhydrolysis between 85-89%). These PVA grades have a molecular weight inthe range from 14,000 g/mol to 250,000 g/mol.

Experiments have now shown that it is not only the degree of hydrolysisof the polyvinyl alcohols employed, and thus the crystallinity, thatplays a role for good processability in tablet formulations, but alsothe physical properties and appearance forms of the commercial PVAgrades employed.

As has already been indicated above, polyvinyl alcohols having acorrespondingly high degree of hydrolysis are only directly tabletableunder particular conditions, i.e. granulation steps have to be carriedout in advance or the PVAs employed must be mixed with further tabletingaids and easily compressible binders, so that the proportion ofpolyvinyl alcohol in the composition as a whole is reduced.

Experiments have surprisingly now shown that particularly fine-grainedpolyvinyl alcohols can be made accessible to direct tabletability.Correspondingly fine-grained polyvinyl alcohols can be obtained ifsuitable polyvinyl alcohols which have been certified for use inpharmaceutical formulations are ground and sieved.

In this way, it is possible to prepare directly tabletable mixturescomprising PVA powder in which the content of PVAs can be setsurprisingly high.

The experiments carried out have also shown that the tabletability ofthe polyvinyl alcohols pretreated in this way can be improved further bycombining them in a suitable manner with further polymeric assistants.This means that the ground, fine-grained powders can subsequently becombined with further, suitable polymeric assistants, causing thecompressibility of the co-mixture obtained to be improved still further.

It has been found here that particularly readily tabletable combinationsare obtained if the ground, fine-grained polyvinyl alcohols are mixedwith microcrystalline celluloses. To this end, use can be made ofcommercially available, microcrystalline celluloses which have beencertified for use in pharmaceutical formulations, such as, for example,the grades Vivapur® 102 and Emcocel® from JRS Pharma and the gradeAvicel® PH 102 from FMC Bioplymer. In particular if the microcrystallinecelluloses used are particularly fine-grained, a considerably improvedcompressibility of the co-mixtures is evident.

This is of particular importance for the development of directlycompressible retard tablets, since the pharmaceutical formulationscientist is always in need of even “better assistants”, i.e. matriceshaving further-improved compressibilities. This is due to the fact thatit is an aim to be able to process even extremely poorly compressibleAPIs in a direct tableting process, which, however, does not succeedwith the DC material of lower compressibility.

In addition, on use of a directly compressible tableting matrix havingimproved compressibility, its use amount can be reduced, enabling theproduction of tablets of lower weight and reduced dimensions, where thetablets obtained also furthermore have very good tablet hardnesses(so-called “dilution effect”). These properties are interesting, inparticular, for so-called “high-dose” retard tablets, since the reducedtablet dimensions improve swallowing by the patient here and thus ensurecompliance and consequently therapeutic success.

Surprisingly, the experiments in the testing of the tabletability ofground PVA grades with various microcrystalline celluloses (MCCs) haveshown that an impairment or alternatively an improvement in thecompressibility can occur, depending on the MCC grade used. Inparticular, the grades Avicel PH105, Vivapur 101 and Avicel PH101 causea significant increase in the tablet hardnesses compared with other MCCgrades—at the same pressing forces. More detailed investigations ofthese MCC grades have shown that they differ from the other gradesthrough their particle sizes. The particle size of these MCCs arepreferably in the D_(v50) range: 17-67 μm. It has been found that thefiner the MCC particle size, the better tablet hardnesses are achievedin combination with fine-grained PVAs. The MCC grades having particlesizes as far as possible smaller than 100 μm should therefore preferablybe used for the preparation of the co-mixtures according to theinvention, particularly preferably those having average particle sizessmaller than 70 μm, especially preferably smaller than 20 μm, measuredas D_(v50) by laser diffraction. On use of “coarser-grained” MCCs (from100 μm and in particular from 180 μm), by contrast, the tablethardnesses drop significantly.

It has been found to be particularly surprising in this connection thatvery apparently only the MCCs are suitable for achieving these improveddirect compression properties; other excipients which usually promotedirect compression, such as, for example, directly compressible calciumhydrogen-phosphates, including Fujicalins® (Fuji Cemical Industry,Japan), directly compressible sorbitols (for example Parteck® SI 400,Merck KGaA, Germany), directly compressible mannitols (for exampleParteck® M200, Merck KGaA, Germany) or directly compressible starches(for example starch 1500, Colorcon Limited, UK), do not exhibit thiseffect in combination with PVAs and do not result in directlycompressible powder mixtures with the PVAs, as our own investigationshave shown.

This effect which has surprisingly been found enables the pharmaceuticalformulation scientist now to be provided with a directly compressiblepremix, predominantly consisting of PVA and fine-grainedmicrocrystalline cellulose, for the production of tablets which canresult in acceleration of a development process of a new tabletformulation.

The improvement in the tablet hardnesses at a constant PVA/MCC ratio inthe direct-compression matrix provides the formulation scientist withthe possibility of also converting active compounds which hitherto couldonly be compressed with difficulty or not at all into a retard tablet.It is furthermore now also possible for him to convert high-dose APIsinto a “patient-friendly” retard tablet having dimensions which caneasily be swallowed. In addition, it is now possible, if required, toreduce the amount of microcrystalline cellulose for the same amount ofPVA and thus to reduce the tablet weight and the tablet dimensionswithout changing the retardation effect of the PVA. These materialsresult in a better dissolution effect than comparative materials basedon coarser-grained MCC grades.

Microcrystalline cellulose (MCC) is one of the most important tabletingaids in the production of pharmaceuticals and is preferably employed asactive compound excipient and is an essential component for oral dosageforms of virtually any type, such as tablets, capsules, sachets,granules and others. In pure form, microcrystalline cellulose (MCC)having the general formula (C₆H₁₀O₅)_(n) is white, free-flowingcellulose in powder form which is commercially available with variousparticle sizes. In pharmaceutical grade, it meets the USP standards.Microcrystalline cellulose serves, inter alia, as indigestible,non-resorbable ballast substance for calorie-reduced foods, for examplesalad dressings, desserts and ice creams, as release agent or asexcipient. As stated in the above description, it is used in pharmacy asa binder or excipient for the production of tablets. In this connection,it has proven particularly suitable for direct tableting and results inhard tablets which have short disintegration times given suitableformulation.

MCC is obtained from woody plant parts (not from waste paper). Plantcellulose is freed from non-crystalline cellulose components usingdilute hydrochloric acid at temperatures above 100° C. This means thatpharmaceutical grade MCC can be obtained by partial hydrolysis of highlypure cellulose and subsequent purification and drying. The hydrolysiscan optionally be followed by carboxylation in order to improve thehydrophilic properties.

MCC is insoluble in water, alcohols and organic solvents. In water, MCCforms a three-dimensional matrix consisting of innumerable, insolublemicrocrystals, which form a stable thixotropic gel. The advantageousproperties of MCC are also retained in the case of temperature-inducedchanges in the phase state, for example on transition into the frozenstate or on heating to elevated temperatures, meaning that MCC isparticularly highly suitable for ready mixes for further processing.

Suitable MCCs for achieving adequate tablet hardnesses have proven to bethe commercially available grades which have average particle sizesD_(v50) if possible less than 100 μm, preferably less than 70 μm,particularly preferably in the D_(v50) range: 17-67 μm, especiallypreferably less than 20 μm, measured as D_(v50) by laser diffraction.Fine-grained MCC grades of this type preferably have bulk densities inthe range from 0.20 to 0.35 g/cm³, preferably in the range from 0.20 to0.31 g/cm³. Suitable commercially available MCC grades which meet thesecriteria and have been qualified for use in pharmaceutical formulationsare, for example,

Vivapur 101 (dried in a stream of air, average particle size D_(v50) 65μm, determined by laser diffraction, bulk density 0.26-0.31 g/cm³),Avicel PH 101 (average particle size 50 μm, bulk density 0.26-0.31g/cm³) and Avicdl PH 105 (spray-dried, average particle size D_(v50) 20μm, determined by laser diffraction, bulk density 0.20-0.30 g/cm³).

However, other commercial products not mentioned here which meet therequirements described can also be used in accordance with the inventiondescribed here.

It is particularly surprising that combination of suitablemicrocrystalline celluloses with various PVA grades, in particular withPVAs having a very wide variety of viscosities, gives directlycompressible mixtures which, if necessary, consist predominantly ofPVAs, but optionally also of equal proportions of PVAs andmicrocrystalline celluloses. If desired, however, it is also possible toemploy mixtures in which the proportion of the fine-grainedmicrocrystalline celluloses is higher than that of the fine-grainedpolyvinyl alcohols.

It has proven particularly advantageous for the ratio of thefine-grained polyvinyl alcohols and fine-grained microcrystallinecelluloses described in the compositions according to the invention tobe in the range 5:1 to 1:5, based on the weight, preferably in a ratioin the range from 2:1 to 1:2, especially preferably in a ratio in theregion of 1:1. Such co-mixtures have proven particularly suitable forthe production of tablets having delayed release of active compound.After intensive mixing, the co-mixtures found here of PVA with MCCs havebulk densities in the range 0.38-0.48 g/ml with tapped densities in therange 0.53-0.65 g/ml.

The advantageous properties described of the combinations offine-grained polyvinyl alcohols and fine-grained microcrystallinecelluloses provide the formulation scientist in the pharmaceuticalindustry, but also in the food industry or in other technical areas,with a material which significantly simplifies the development effortfor solid compressed administration forms having extended release ofactive compound. He needs only mix his active compound to be retardedwith the PVA/MCC combination according to the invention, optionally adda few assistants, in particular lubricants, and then compress thismixture in a tableting machine. The particularly good tabletingproperties of this matrix have also facilitated the development ofretard tablets with active compounds which per se are actually notregarded as directly compressible and had to be granulated in advance inprocesses carried out in a conventional manner. The use of this PVA/MCCmatrix saves development time, investment in equipment and results inimproved process reliability in development and production.

An advantageous side effect arises on use of the co-mixtures accordingto the invention in the tableting process, which consists in that themixtures according to the invention result in comparatively low ejectionforces, enabling significantly smaller amounts of lubricants to be usedthan is otherwise usual in tableting. Thus, instead of the usualaddition of 1% of magnesium stearate, only about a quarter of thisamount is required, in some cases even less. Under particularconditions, the addition of such lubricants can also be omittedentirely. This causes an additional improvement in the interparticularbinding forces, i.e. harder tablets are obtained for the same pressingforce, enabling reproducible release of active compound to be achieved.The latter is due to the fact that the release is essentially controlledvia the PVA content, and the addition of a small amount of hydrophobicmagnesium stearate only exerts a slight influence on the releasebehaviour.

Furthermore, the present invention relates to a process for influencingthe tableting properties of fine-grained PVA grades, in particular ofground PVAs, which have per se only low compressibilities. Experimentshave shown that these fine-grained PVAs can be converted into a directlycompressible form by combination with fine-grained MCCs.

Fine-grained PVAs are particularly suitable for use as retardationmatrices, since they can generally be employed very well in order toprepare more homogeneous mixtures with the active compound to beretarded. The latter is of particular importance for the single dosageaccuracy “content uniformity” in order always to obtain the same amountof active compound in each individual tablet.

In addition, this type of formulation with fine-grained PVA grades hasthe advantage that the large surface areas of the fine PVA particlesresults in more homogeneous gel layer formation after moistening in thegastro-intestinal tract, which, when the tablets have been taken by thepatient, results in more reproducible and possibly also extendeddiffusion of the active compound through this gel.

Procedure

For the preparation of the co-mixtures according to the invention,finely ground polyvinyl alcohols (PVAs) are mixed intensively withselected fine-grained microcrystalline celluloses (MCCs) and thusconverted into co-mixtures which are eminently suitable as directlycompressible tableting matrices. This is particularly surprising sinceblends of such PVAs with other directly tabletable assistants—also veryreadily compressible per se—on the market do not exhibit this directcompression effect with the pulverulent PVAs, in particular also notwith any desired microcrystalline celluloses. Only when fine-grainedPVAs are combined with particularly fine-grained microcrystallinecelluloses are directly compressible co-mixtures obtained.

With these fine-grained co-mixtures according to the invention, activecompounds which are poorly compressible per se can advantageously beconverted into formulations which can very readily be compressed to givetablets without further preparations. Furthermore, it can be shown withthe tablets produced which comprise corresponding co-mixtures as activecompound excipient, that the active compound can be released in acontrolled manner over a very long time from tablets produced in thisway. The corresponding active compound-containing tablets exhibitdelayed releases of active compound of at least 2 hours, preferably ofover at least 6 hours, particularly preferably of at least 8 hours,especially preferably of at least 10 hours, and very particularlypreferably releases of active compound of up to 12 hours, depending onthe active compound employed and on the mixing ratio of the fine-grainedpolyvinyl alcohols with the microcrystalline celluloses.

Since the term “directly compressible” is not defined in a bindingmanner in connection with the preparation of tablet formulations, thepressing behaviour of a commercial as very readily compressible mannitol(Parteck® M 200 (mannitol), suitable for use as excipient EMPROVE® expPh. Eur, BP, JP, USP, E 421, Article No. 1.00419, Merck KGaA, Darmstadt,Germany) is used in the present description as standard for comparison.The aim is to come as close as possible to the behaviour of Parteck® M200 with respect to its compressibility by means of the directlycompressible co-mixtures which comprise fine-grained PVAs withfine-grained microcrystalline celluloses in relatively large amount.

The experiments carried out have shown that active compound-containingtablets which comprise a composition according to the invention in theform of a co-mixture in an amount of 1-99% by weight, preferably in anamount of 5-95% by weight, very particularly preferably in an amount of10-90% by weight, based on the total weight of the tablet, have thedesired, particularly good compressibility. Tablets having particularlyhigh tablet hardnesses which require surprisingly low ejection forces inthe production process can advantageously be obtained with suchcompositions as desired even on use of low pressing forces. Even on useof a pressing force of 20 kN, tablets having a tablet hardness of up to462 N are obtained which only require an ejection force of less than 60N. In addition, these tablets have only low friabilities, as can beshown by suitable experiments.

The present invention thus provides a process for the preparation ofdirectly compressible compositions having extended release of activecompound and particularly good compressibility, giving a co-mixture offine-grained microcrystalline celluloses (MCCs) and fine-grainedpolyvinyl alcohols (PVAs) in which polyvinyl alcohol is ground to give afine-grained powder having an average particle size D_(v50) in the rangefrom 50 to 260 μm, a bulk density in the range from 0.55 to 0.62 g/mland an angle of repose in the range from 35 to 38° and is sieved throughan 800 μm sieve, and the powder obtained is mixed with fine-grainedmicrocrystalline celluloses (MCCs) having an average particle sizeD_(v50) in the region <100 μm, preferably having average particle sizesof D_(v50)<70 μm, particularly preferably having average particle sizesin the D_(v50) range 17 to 67 μm, in particular in the D_(v50) range 17μm-20 μm, and having bulk densities in the range from 0.20 to 0.35g/cm³, preferably in the range from 0.20 to 0.31 g/cm³. In this way, adirectly compressible co-mixture is obtained, to which various activecompounds can be added if desired and which can be compressed to givetablets having delayed release of active compound.

The examples given below disclose methods and conditions for thepreparation of PVA/MCC co-mixtures according to the invention. It isself-evident to the person skilled in the art in the area that othermethods for grinding and mixing the starting substances than describedhere are also available.

The examples demonstrate the particular advantages of these fine-grainedPVA/MCC combinations compared with the inadequate compressibilitiesobtained by PVA combinations with other excipients—but ones which areregarded as particularly readily tabletable.

On blending a fine-grained PVA/MCC matrix according to the inventionwith a pulverulent active compound which is poorly compressible per seand addition of a very small amount of magnesium stearate as lubricant,tablets of adequate hardnesses with low mechanical abrasion can beobtained by simple direct tableting and are readily available forfurther treatment, for example for packaging in blister packs or forbreak-free removal from these blister packs by the patient.Corresponding active compound-containing tablets show that extendedrelease of active compound from such PVA/MCC matrix tablets over severalhours can be guaranteed.

LIST OF FIGURES

FIGS. 1 to 4 show graphically the experimental results for illustration:

FIG. 1: pressing force/tablet hardness profile (from Table 1b)

FIG. 2: pressing force/tablet hardness profile (from Table 2b)

FIG. 3: pressing force/tablet hardness profile (from Table 3b)

FIG. 4: pressing force/tablet hardness profile (from Table 4b)

EXAMPLES

The present description enables the person skilled in the art to applythe invention comprehensively. Even without further comments, it istherefore assumed that a person skilled in the art will be able toutilise the above description in the broadest scope.

If anything is unclear, it goes without saying that the publications andpatent literature cited should be consulted. Accordingly, thesedocuments are regarded as part of the disclosure content of the presentdescription.

For better understanding of the invention and in order to illustrate it,examples are given below which are within the scope of protection of thepresent invention. These examples also serve to illustrate possiblevariants. Owing to the general validity of the inventive principledescribed, however, the examples are not suitable for reducing the scopeof protection of the present application to these alone.

Furthermore, it goes without saying to the person skilled in the artthat, both in the examples given and also in the remainder of thedescription, the component amounts present in the compositions alwaysonly add up to 100% by weight or mol-%, based on the composition as awhole, and cannot exceed this, even if higher values could arise fromthe per cent ranges indicated. Unless indicated otherwise, % data arethus regarded as % by weight or mol-%, with the exception of ratios,which are reproduced in volume figures.

The temperatures given in the examples and the description as well as inthe claims are in ° C.

The conditions for the preparation of the specific PVA/MCC combinationaccording to the invention arise from the various examples. The MCCgrades Avicel PH105 (Examples A1-A4) and Avicel PH101 (Examples C1-C4)from FMC Biopolymer and the grade Vivapur 101 (Examples B1-B4) from JRSPharma are very particularly suitable. With these materials, the hardesttablets are obtained on use of comparable pressing forces, i.e thesespecific combinations exhibit the best “dilution” potential.

Characterisation of the Materials Used

1. PVA Grade Used and Their Properties:

1.1 Raw Materials for Grinding

-   1.1.1. PVA 4-88: polyvinyl alcohol 4-88, suitable for use as    excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41350,    Merck KGaA, Darmstadt, Germany-   1.1.2. PVA 18-88: polyvinyl alcohol 18-88, suitable for use as    excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41355,    Merck KGaA, Darmstadt, Germany-   1.1.3. PVA 26-88: polyvinyl alcohol 26-88, suitable for use as    excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41352,    Merck KGaA, Darmstadt, Germany-   1.1.4. PVA 40-88: polyvinyl alcohol 40-88, suitable for use as    excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41353,    Merck KGaA, Darmstadt, Germany-   1.1.5. PVA 28-99: polyvinyl alcohol 28-99, suitable for use as    excipient EMPROVE® exp JPE, Article No. 1.41356, Merck KGaA,    Darmstadt, Germany

These PVA grades are in the form of coarse particles—having a size ofseveral millimetres—which in this form cannot be employed as a directlycompressible tableting matrix.

The large particles do not allow reproducible filling of the dies andthus also do not allow a constant tablet weight at high rotationalspeeds of the (rotary) tableting machines. In addition, onlyfine-grained PVAs are able to ensure homogeneous distribution of theactive compound without the occurrence of separation effects in thetablets. This is absolutely necessary for ensuring individual dosageaccuracy of the active compound (content uniformity) in each tabletproduced. In addition, only a fine-grained PVA can also ensure thehomogeneous gel formation throughout the tablet body that is necessaryfor reproducible retardation.

For these reasons, the above-mentioned coarse-grained PVA grades must becomminuted, i.e. ground, before use as directly compressible retardationmatrices,

1.2 Ground PVA Grades

1.2.1. Ground PVA 4-88, from polyvinyl alcohol 4-88 Article No. 1.413501.2.2. Ground PVA 18-88, from polyvinyl alcohol 18-88 Article No.1.41355 1.2.3. Ground PVA 26-88, from polyvinyl alcohol 26-88 ArticleNo. 1.41352 1.2.4. Ground PVA 40-88, from polyvinyl alcohol 40-88Article No. 1.41353 1.2.5. Ground PVA 28-99, from polyvinyl alcohol28-99 Article No. 1.41356

Grinding:

The grinding of the PVA grades is carried out in an Aeroplex 200 ASspiral jet mill from Hosokawa Alpine, Augsburg, Germany, under liquidnitrogen as cold grinding from 0° C. to minus 30° C.,

The resultant product properties of the ground PVA grades, in particularthe powder characteristics, such as bulk density, tapped density, angleof repose, BET surface area, BET pore volume and the particle sizedistributions, are evident from the following tables:

Bulk density, tapped density, angle of repose, BET surface area, BETpore volume:

(details on the measurement method, see under Methods)

Bulk Tapped Angle of BET surface BET pore density density repose areavolume Sample (g/ml) (g/ml) (°) (m²/g) (cm³/g) PVA 4-88* 0.61 0.82 35.10.1308 0.0008 PVA 18-88* 0.57 0.76 35.5 0.1831 0.0011 PVA 26-88* 0.560.74 35.5 0.2045 0.0013 PVA 40-88* 0.59 0.77 36.9 0.1123 0.0009 PVA28-99* 0.58 0.76 37.7 0.2210 0.0016 *ground PVA

Particle distribution determined by laser diffraction with dry dispersal(1 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 4-88* 21.36 33.9360.39 75.25 91.61 177.74 380.57 790.37 PVA 18-88* 29.67 44.93 73.9589.11 105.22 185.49 375.88 755.84 PVA 26-88* 27.76 42.32 73.01 90.14108.67 198.51 382.65 676.96 PVA 40-88* 31.84 50.64 89.13 109.77 131.45230.52 413.71 634.59 PVA 28-99* 24.87 39.81 72.81 90.72 109.31 191.42343.54 561.23 *ground PVA

Particle distribution determined by laser diffraction with dry dispersal(2 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 4-88* 19.09 30.2152.69 64.83 77.87 143.83 279.64 451.94 PVA 18-88* 26.90 40.38 65.3 78.0891.55 159.10 321.46 607.64 PVA 26-88* 24.59 36.93 61.67 75.05 89.33157.79 286.17 434.23 PVA 40-88* 31.03 49.47 88.54 110.06 132.79 235.87430.35 686.1 PVA 28-99* 24.27 39.63 74.31 93.13 112.51 196.45 350.21570.12 *ground PVA

Particle distribution determined by laser diffraction with dry dispersal(3 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 4-88* 18.35 29.2751.25 63.09 75.77 139.46 269.8 425.62 PVA 18-88* 24.55 36.60 57.91 68.4879.45 132.37 246.56 393.59 PVA 26-88* 25.17 38.18 64.35 78.47 93.57167.41 317.16 514.18 PVA 40-88* 32.81 53.33 96.27 119.61 144.21 256.31463.67 717.76 PVA 28-99* 22.33 35.92 65.94 82.31 99.37 174.84 305.5454.03 *ground PVA

Particle distribution determined by laser diffraction with wet dispersal(in low-viscosity silicone oil):

figures in μm (details on the measurement method, see under Methods)

Muster Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 4-88* 10.03 20.1 38.0247.82 58.31 110.91 231.64 390.95 PVA 18-88* 17.19 30.25 50.06 59.2268.47 111.89 212.70 357.70 PVA 26-88* 15.42 26.76 45.50 54.83 64.47110.50 212.91 353.68 PVA 40-88* 20.41 34.80 60.35 73.32 86.96 154.96299.57 490.08 PVA 28-99* 14.68 25.96 47.49 58.88 70.80 127.68 240.70376.70 *ground PVA

Particle distribution determined by tower sieving:

figures in percent by weight (details on the measurement method, seeunder Methods)

32- 50- 75- 100- 150- 200- <32 50 75 100 150 200 250 Sample μm μm μm μmμm μm μm PVA 4-88* 3.3 7.9 12.6 12.2 19.6 12.9 10.5 PVA 18-88* 0.5 8.112.8 13.6 20.4 15.0 9.4 PVA 26-88* 5.3 8.4 12.3 13.6 21.8 13.1 9.0 PVA40-88 2.6 5.5 8.1 8.8 17.8 14.0 10.7 PVA 28-99* 5.0 7.1 9.1 9.8 20.413.2 11.7 250- 300- 355- 400- 500- 600- 300 355 400 500 600 710 >710Sample μm μm μm μm μm μm μm PVA 4-88* 6.5 4.5 2.8 3.5 2.0 0.9 0.8 PVA18-88* 5.8 4.2 2.6 3.5 2.1 1.0 1.0 PVA 26-88* 5.0 3.7 2.2 2.7 1.8 0.60.5 PVA 40-88 7.5 6.6 3.9 5.9 4.1 1.9 2.6 PVA 28-99* 7.9 5.3 3.2 3.7 2.00.8 0.8 *ground PVA

2. Microcrystalline Celluloses (MCCs) the Preparation of the Blends WithPolyvinyl Alcohols (Ground)

2.1 Avicel ® PH 101, microcrystalline cellulose, Ph. Eur., NF, JP, FMCBioPolymer, USA 2.2 Avicel ® PH 102, microcrystalline cellulose, Ph.Eur., NF, JP, FMC BioPolymer, USA 2.3 Avicel ® PH 102 SCG,microcrystalline cellulose, Ph. Eur., NF, JP, FMC BioPolymer, USA 2.4Avicel ® PH 105, microcrystalline cellulose, Ph. Eur., NF, JP, FMCBioPolymer, USA 2.5 Vivapur ® Type 12, microcrystalline cellulose, Ph.Eur., NF, JP, JRS Pharma, Rosenberg, Germany 2.6 Vivapur ® Type 101,microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg,Germany 2.7 Vivapur ® Type 102 Premium, microcrystalline cellulose, Ph.Eur., NF, JP, JRS Pharma, Rosenberg, Germany 2.8 Vivapur ® Type 200,microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg,Germany 2.9 Emcocel ® 90 M, microcrystalline cellulose, Ph. Eur., NF,JP, JRS Pharma, , Rosenberg, Germany 2.10 Emcocel ® LP 200,microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, , Rosenberg,Germany 2.11 Comprecel ® M 302, microcrystalline cellulose, Ph. Eur.,NF, JP, BP, USP, Mingtai Chemical Co. Ltd., Taiwan

Particle distribution determined by laser diffraction with dry dispersal(1 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Avicel ® PH 101 22.59 33.0937.77 42.36 61.82 98.62 161.34 Avicel ® PH 102 28.27 46.75 56.59 66.56107.27 170.38 235.70 Avicel ® PH 102 SCG 48.99 90.03 106.32 120.84173.66 251.80 331.64 Avicel ® PH 105 6.80 10.21 11.61 12.94 18.50 28.3540.38 Vivapur ® 12 42.55 75.61 92.59 108.97 171.37 264.07 358.09Vivapur ® 101 20.66 30.70 35.97 41.53 66.58 108.89 155.53 Vivapur ® 10231.56 53.04 66.00 79.89 135.87 215.53 293.94 Vivapur ® 200 49.25 97.09125.64 152.47 245.21 375.17 507.15 Emcocel ® 90 M 41.28 63.99 73.8983.41 121.96 185.25 253.79 Emcocel ® LP 200 68.47 113.69 129.77 144.39199.67 285.27 376.22 Comprecel ® M 302 30.07 55.56 66.85 77.23 116.30176.60 240.36

Particle distribution determined by laser diffraction with dry dispersal(2 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Avicel ® PH 101 19.43 28.5532.60 36.53 52.81 80.77 114.13 Avicel ® PH 102 28.40 47.32 57.45 67.69108.91 171.94 236.64 Avicel ® PH 102 SCG 48.32 84.95 100.38 114.43166.33 243.47 321.96 Avicel ® PH 105 6.39 9.81 11.19 12.52 18.03 27.7739.70 Vivapur ® 12 35.98 62.68 77.81 93.33 155.79 249.72 345.23Vivapur ® 101 19.61 29.42 34.61 40.15 66.06 113.18 176.82 Vivapur ® 10227.55 45.97 57.41 70.40 127.29 208.92 288.93 Vivapur ® 200 44.08 86.21113.63 140.90 235.62 365.86 497.34 Emcocel ® 90 M 37.39 58.75 68.0877.03 113.34 173.41 239.37 Emcocel ® LP 200 75.97 121.31 137.44 152.19208.23 294.84 385.17 Comprecel ® M 302 33.33 62.38 74.56 85.63 127.04190.77 257.84

Particle distribution determined by laser diffraction with dry dispersal(3 bar counterpressure):

figures in μm (details on the measurement method, see under Methods)

Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Avicel ® PH 18.03 26.91 30.9134.81 51.16 80.11 117.89 101 Avicel ® PH 24.28 40.18 49.21 58.86 100.25164.22 229.95 102 Avicel ® PH 42.19 77.05 92.59 106.73 158.55 234.98312.72 102 SCG Avicel ® PH 6.10 9.50 10.88 12.20 17.67 27.29 38.96 105Vivapur ® 31.65 54.13 67.50 81.98 144.53 240.48 338.01  12 Vivapur ®17.23 25.91 30.40 35.18 58.17 99.16 143.94 101 Vivapur ® 23.61 38.8448.19 59.22 114.76 198.37 278.99 102 Vivapur ® 38.43 73.36 97.85 124.94223.50 356.46 490.73 200 Emcocel ® 34.07 55.25 64.57 73.49 109.27 167.95232.86 90 M Emcocel ® 61.18 104.76 120.78 135.31 189.83 272.98 358.76 LP200 Comprecel ® 29.22 54.80 66.28 76.75 115.86 175.96 239.63 M 302 *ground PVA

Particle distribution determined by laser diffraction with wet dispersal(in low-viscosity silicone oil):

figures in μm (details on the measurement method, see under Methods)

Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Avicel ® PH 20.66 32.85 38.1843.31 63.99 98.56 140.53 101 Avicel ® PH 26.92 46.05 55.55 64.77 101.48161.28 227.07 102 Avicel ® PH 38.64 69.23 83.63 97.33 150.39 231.75316.41 102 SCG Avicel ® PH 5.21 9.07 10.51 11.84 17.11 26.17 37.37 105Vivapur ® 12 31.45 55.34 67.86 80.26 132.04 219.78 316.04 Vivapur ® 10117.51 26.83 31.53 36.51 59.93 99.84 144.07 Vivapur ® 102 28.28 47.2758.07 69.46 119.03 200.35 285.42 Vivapur ® 200 33.53 59.12 74.18 90.77171.42 302.56 434.89 Emcocel ® 90 M 35.68 58.96 68.77 78.12 116.55183.76 261.39 Emcocel ® LP 60.38 105.52 122.18 137.35 194.75 283.57377.02 200 Comprecel ® 27.02 52.05 63.61 74.24 114.48 178.54 248.78 M302

2. Other Materials

Since the term “directly compressible” is not defined in a bindingmanner, the pressing behaviour of a commercial very readily compressiblemannitol is employed as standard:

Parteck® M 200 (mannitol), suitable for use as excipient EMPROVE® expPh. Eur., BP, JP, USP, E 421, Article No. 1.00419, Merck KGaA,Darmstadt, Germany

The aim is to come as close as possible to the behaviour of Parteck® M200 by means of the directly compressible PVAs, in particular withrespect to their compressibility.

Equipment/Methods for Characterisation of the Substance Properties

1. Bulk density: in accordance with DIN EN ISO 60: 1999 (German version)

-   -   quoted in “g/ml”        2. Tapped density: in accordance with DIN EN ISO 787-11: 1995        (German version)    -   quoted in “g/ml”        3. Angle of repose: in accordance with DIN ISO 4324: 1983        (German version)    -   quoted in “degrees”        4. Surface area determined in accordance with BET: evaluation        and procedure in accordance with the literature “BET Surface        Area by Nitrogen Absorption” by S. Brunauer et al. (Journal of        American Chemical Society, 60, 9, 1983) instrument: ASAP 2420        Micromeritics Instrument Corporation (USA); nitrogen; sample        weight: about 3.0000 g; heating: 50° C. (5 h); heating rate        3K/min; quoting of the arithmetic mean from three determinations        5. Particle size determination by laser diffraction with dry        dispersal: Mastersizer 2000 with Scirocco 2000 dispersion unit        (Malvern Instruments Ltd. UK), determinations at a        counterpressure of 1 and 2 bar; Fraunhofer evaluation;        dispersant RI: 1.000, obscuration limits: 0.0-10.0%, tray type:        general purpose, background time: 7500 msec, measurement time:        7500 msec, procedure in accordance with ISO 13320-1 and the        information in the technical manual and specifications from the        instrument manufacturer; result given in % by vol.        6. Particle size determination by laser diffraction with wet        dispersal: Mastersizer 2000 with Hydro 2000SM wet-dispersion        unit (Malvern Instruments Ltd., UK); dispersion medium        low-viscority silicone oil (manufacturer: Evonic Goldschmidt        GmbH, Germany; manufacturer's name: Tegiloxan3, manufacturer's        article no.: 9000305); dispersant RI: 1.403; stirrer speed: 2500        rpm; tray type: general purpose; background time: 7500 msec;        measurement time: 7500 msec; obscuration limits: 7.0-13.0%;        procedure in accordance with ISO 13320-1 and the information in        the technical manual and specifications from the instrument        manufacturer; result given in % by vol.        Procedure: the suspension cell is filled with the low-viscosity        silicone oil, the sample is added in portions until the target        obscuration range (7.0-13.0%) has been reached, and the        measurement is started after a waiting time of 2 minutes.        7. Particle size determination by dry sieving via a sieve tower:        Retsch AS 200 control, Retsch (Germany); amount of substance:        about 110.00 g; sieving time: 30 minutes; amplitude intensity: 1        mm; interval: 5 seconds; analytical sieve with metal-wire fabric        in accordance with DIN ISO 3310; mesh widths (in μm): 710, 600,        500, 400, 355, 300, 250, 200, 150, 100, 75, 50, 32; amount        distribution per sieve fraction indicated in the tables as “% by        weight of the sample weight”:        8. The tableting tests are carried out as follows:

The mixtures in accordance with the compositions indicated in theexperimental part are mixed for 5 minutes in a sealed stainless-steelcontainer (capacity: about 2 l, height: about 19.5 cm, diameter: about12 cm outside dimension) in a laboratory tumble mixer (Turbula T2A,Willy A. Bachofen, Switzerland).

The magnesium stearate employed is Parteck LUB MST (vegetable magnesiumstearate) EMPROVE exp Ph. Eur., BP, JP, NF, FCC Article No. 1.00663(Merck KGaA, Germany) which has been passed through a 250 μm sieve.

The compression to give 500 mg tablets (11 mm punch, round, flat, withbevel edge) is carried out in a Korsch EK 0-DMS instrumented eccentrictableting machine (Korsch, Germany) with the Catman 5.0 evaluationsystem (Hottinger Baldwin Messtechnik—HBM, Germany).

Depending on the pressing force tested (nominal settings: ˜5, ˜10, ˜20and ˜30 kN; the effectively measured actual values are indicated in theexamples), at least 100 tablets are produced for evaluation of thepressing data and determination of the pharmaceutical formulationcharacteristic values.

Tablet hardnesses, diameters and heights: Erweka Multicheck 5.1 (Erweka,Germany); average data (arithmetic means) from in each case 20 tabletmeasurements per pressing force. The measurements are carried out oneday after the tablet production.

Tablet abrasion: TA420 friability tester (Erweka, Germany); instrumentparameters and performance of the measurements in accordance with Ph.Eur. 7^(th) Edition “Friability of Uncoated Tablets”. The measurementsare carried out one day after tablet production.

Tablet weight: Average value (arithmetic mean) from the weighing of 20tablets per pressing force: Multicheck 5.1 (Erweka, Germany) withSartorius CPA 64 balance (Sartorius, Germany). The measurements arecarried out one day after tablet production.

Experimental Results

The experiments have shown that, in particular, only the co-mixtureswith three specific microcrystalline celluloses (MCCs) result in goodcompressibility.

The experiments have also shown that apparently not all commerciallyavailable MCC grades exhibit an improvement in the compressibility inthe co-mixtures with ground PVAs.

Since the turn “directly compressible” is not defined in a bindingmanner, the pressing behaviour of a commercial mannitol which as veryreadily compressible (Parteck® M 200 (mannitol)), suitable for use asexcipient EMPROVE® exp Ph. Eur., BP, JP, USP, E 421, Catalogue No,100419, Merck KGaA, Darmstadt, Germany) is set as standard. The aim isto come as close as possible to the behaviour of Parteck® M200 with thedirectly compressible PVAs (as co-mixtures), in particular with respectto their compressibility.

The experiments have shown that co-mixtures based on finely groundpolyvinyl alcohols with the fine-grained microcrystalline celluloses,such as, for example, with the commercially available products Avicel PH105 (Examples A1-A4), Vivapur 101 (Examples B1-B4) and Avicel PH101(Examples C1-C4) have very particularly good compressibility. Thiscompressibility is equivalent or even significantly better than that ofParteck® M200, which is regarded as particularly readily directlycompressible.

These specific PVA/MCC co-mixtures are thus particularly highly suitablein direct tableting as matrices for the formulation of retard tablets incombination with active compounds which are poorly compressible per se.

Procedure

1a.

Preparation of the blends consisting of the various commercialmicrocrystalline celluloses with the ground PVA grade 4-88

1b.

Pressing of these blends (with addition of 0.25% by weight of Parteck®LUB MST) and tablet characterisation with respect to the parameterstablet hardness, tablet weight, tablet height, tablet abrasion andejection force necessary

2a.

Preparation of the blends consisting of the various commercialmicrocrystalline celluloses with the ground PVA grade 18-88

2b.

Pressing of these blends (with addition of 0.25% by weight of Parteck®LUB MST) and tablet characterisation with respect to the parameterstablet hardness, tablet weight, tablet height, tablet abrasion andejection force necessary

3a.

Preparation of the blends consisting of the various commercialmicrocrystalline celluloses with the ground PVA grade 26-88

3b.

Pressing of these blends (with addition of 0.25% by weight of Parteck®LUB MST) and tablet characterisation with respect to the parameterstablet hardness, tablet weight, tablet height, tablet abrasion andejection force necessary

4a.

Preparation of the blends consisting of the various commercialmicrocrystalline celluloses with the ground PVA grade 40-88

4b.

Pressing of these blends (with addition of 0.25% by weight of Parteck®LUB MST) and tablet characterisation with respect to the parameterstablet hardness, tablet weight, tablet height, tablet abrasion andejection force necessary

Experimental Results

1a. Preparation of the blends of the directly compressible excipientswith the ground PVA grade 4-88

General description: ground PVA 4-88 is passed through an 800 μm handsieve in order to remove any coarse components and agglomerates. 300 gof this sieved product are weighed out into a 2 l Turbula mixing vessel,300 g of the corresponding microcrystalline cellulose from Table 1a areadded and mixed for 5 min. in a T2A Turbula mixer.

TABLE 1a Composition of the co-mixtures of around PVA 4-88 withmicrocrystalline celluloses Composition 50% by weight of PVA 50% byweight of MCC Example A1 PVA 4-88* Avicel ® PH 105 Example B1 PVA 4-88*Vivapur ® 101 Example C1 PVA 4-88* Avicel ® PH 101 Comparison D1 PVA4-88* Vivapur ® 12 Comparison E1 PVA 4-88* Vivapur ® 102 PremiumComparison F1 PVA 4-88* Vivapur ® 200 Comparison G1 PVA 4-88* Emcocel ®LP200 *ground PVA

1b. Compression of these blends and tablet characterisation

Gen. description: 1.25 g of magnesium stearate are added to in each case498.75 g of the co-mixtures of Examples A1-C1 or Comparisons D1-G1prepared above in a Turbula mixing vessel, the mixture is mixed againfor 5 min. in a T2A Turbula mixer and tabletted in a Korsch EK 0-DMSeccentric press.

The comparison used is Parteck® M200 blended with 1% of Parteck®LUB MST.Note: compression of Parteck® M200 with less magnesium stearate is notpossible owing to the very high ejection forces which otherwise result.

TABLE 1b Tableting data of the co-mixtures of ground PVA 4-88 withmicrocrystalline celluloses A Nominal Actual B C D E F Example A1 5 4.9102.7 498.6 5.4 0.24 103.3 10 10.4 230.8 493.1 4.8 0 110.1 20 19.5 439.4486.6 4.4 0 70.4 30 30.3 551.5 486.9 4.3 0 48.6 Example B1 5 5.1 89.6500.8 5.5 0.43 90.1 10 9.5 192.7 500.4 4.9 0.16 94.6 20 21.4 390.1 504.94.5 0.07 58.8 30 29.5 447.6 504.3 4.4 0.07 51.2 Example C1 5 4.9 77.9495.1 5.6 0.69 96.8 10 9.8 178.6 497.8 4.9 0.16 98.7 20 21.1 340.5 501.64.5 0.06 61.7 30 30.9 405.0 503.6 4.4 0.05 50.7 Comparison 5 5.0 45.8495.8 5.4 1.47 86.6 D1 10 10.6 107.0 500.5 4.9 0.27 97.5 20 20.2 208.9502.0 4.4 0.08 75.4 30 30.7 250.8 502.4 4.4 0.07 66.4 Comparison 5 5.165.2 501.3 5.5 0.55 — E1 10 9.6 140.0 504.8 4.9 0.19 95.9 20 19.8 264.8503.9 4.5 0.10 65.4 30 30.8 321.2 504.7 4.4 0.06 56.3 Comparison 5 5.133.7 497.8 5.5 4.72 75.4 F1 10 9.6 81.2 502.1 5.0 0.59 85.7 20 19.1160.4 503.2 4.6 0.19 62.4 30 30.3 188.8 502.2 4.5 0.14 53.9 Comparison 55.0 22.4 493.4 5.7 47.34 82.0 G1 10 9.7 58.2 498.0 5.0 1.24 91.1 20 20.0121.6 500.4 4.6 0.25 63.8 30 29.6 138.3 500.8 4.5 0.21 54.7 Parteck ® 55.2 84.1 497.8 5.1 0.21 155.8 M200 10 10.7 196.5 500.6 4.6 0.17 306.0 2020.3 340.0 499.4 4.2 0.15 513.6 30 30.0 396.7 498.3 4.0 0.16 647.6 Key:A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tabletweight [mg] D: Tablet height [mm] E: Abrasion [%] F: Ejection force (N)

FIG. 1 shows a graph of the very different pressing force/tablethardness profiles for better illustration.

2a. Preparation of the blends of the directly compressible excipientswith the ground PVA grade 18-88

General description: ground PVA 18-88 is passed through an 800 μm handsieve in order to remove any coarse components and agglomerates. 300 gof this sieved product are weighed out into a 2 l Turbula mixing vessel,300 g of the corresponding microcrystalline cellulose from Table 2a areadded and mixed for 5 min. in a T2A Turbula mixer.

TABLE 2a Composition of the co-mixtures of ground PVA 18-88 withmicrocrystalline celluloses Composition 50% by weight of PVA 50% byweight of MCC Example A2 PVA 18-88* Avicel ® PH 105 Example B2 PVA18-88* Vivapur ® 101 Example C2 PVA 18-88* Avicel ® PH 101 Comparison D2PVA 18-88* Vivapur ® 12 Comparison E2 PVA 18-88* Vivapur ® 102 PremiumComparison F2 PVA 18-88* Vivapur ® 200 Comparison G2 PVA 18-88*Emcocel ® LP200 *ground PVA

2b. Compression of these blends and tablet characterisation

General description:

1.25 g of magnesium stearate are added to in each case 498.75 g of theco-mixtures of Examples A2-C2 or Comparisons D2-G2 prepared above in aTurbula mixing vessel, the mixture is mixed again for 5 min. in a T2ATurbula mixer and tabletted in a Korsch EK 0-DMS eccentric press.

The comparison used is Parteck® M200 blended with 1% of Parteck® LUBMST. Note: compression of Parteck® M200 with less magnesium stearate isnot possible owing to the very high ejection forces which otherwiseresult.

TABLE 2b Tableting data of the co-mixtures of ground PVA 18-88 withmicrocrystalline celluloses A Nominal Actual B C D E F Example 5 5.6120.0 501.1 5.4 0.08 107.2 A2 10 10.3 239.1 501.9 4.9 0 108.8 20 20.5465.5 502.2 4.5 0 69.5 30 31.1 591.0 497.2 4.3 0 49.2 Example 5 4.8 82.2497.9 5.5 0.44 83.6 B2 10 9.4 184.2 497.3 4.9 0.12 89.4 20 21.0 363.8498.6 4.4 0.04 58.1 30 30.5 448.5 500.9 4.3 0.02 49.4 Example 5 5.1 73.0497.5 5.4 0.59 92.6 C2 10 10.3 172.5 501.5 4.9 0.13 94.6 20 19.6 311.5503.7 4.5 0.05 66.1 30 31.2 401.2 504.8 4.4 0.03 52.0 Comparison 5 5.335.7 498.1 5.6 2.51 87.3 D2 10 9.8 98.2 502.2 4.9 0.25 95.7 20 20.8181.8 504.5 4.5 0.07 66.9 30 31.5 218.8 504.5 4.4 0.02 57.8 Comparison 55.5 66.7 498.6 5.4 0.45 91.6 E2 10 10.1 139.1 501.2 4.9 0.13 94.1 2020.8 264.3 503.8 4.5 0.06 66.6 30 28.8 304.7 502.5 4.4 0.02 60.0Comparison 5 4.9 26.1 493.6 5.6 7.70 74.5 F2 10 9.8 70.8 499.7 5.0 0.6186.4 20 20.7 149.1 501.5 4.5 0.16 65.5 30 29.8 176.1 502.5 4.5 0.12 59.5Comparison 5 5.4 18.9 495.4 5.7 100.0 83.0 G2 10 9.8 45.4 502.2 5.1 1.5790.8 20 19.2 104.2 504.1 4.6 0.22 69.1 30 29.8 126.5 506.1 4.5 0.14 59.0Parteck ® 10 5.2 84.1 497.8 5.1 0.21 155.8 M200 10.7 196.5 500.6 4.60.17 306.0 20.3 340.0 499.4 4.2 0.15 513.6 30.0 396.7 498.3 4.0 0.16647.6 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C:Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Ejectionforce (N)

FIG. 2 shows a graph of the very different pressing force/tablethardness profiles for better illustration.

3a. Preparation of the blends of the directly compressible excipientswith the ground PVA grade 26-88

General description: ground PVA 26-88 is passed through an 800 μm handsieve in order to remove any coarse components and agglomerates. 300 gof this sieved product are weighed out into a 2 l Turbula mixing vessel,300 g of the corresponding microcrystalline cellulose from Table 3a areadded and mixed for 5 min. in a T2A Turbula mixer.

TABLE 3a Composition of the co-mixtures of ground PVA 26-88 withmicrocrystalline celluloses Composition 50% by weight of PVA 50% byweight of MCC Example A3 PVA 26-88* Avicel ® PH 105 Example B3 PVA26-88* Vivapur ® 101 Example C3 PVA 26-88* Avicel ® PH 101 Comparison D3PVA 26-88* Avicel ® PH 102 Comparison E3 PVA 26-88* Avicel ® PH 102 SCGComparison F3 PVA 26-88* Vivapur ® 12 Comparison G3 PVA 26-88* Vivapur ®102 Premium Comparison H3 PVA 26-88* Vivapur ® 200 Comparison I3 PVA26-88* Emcocel ® 90M Comparison J3 PVA 26-88* Emcocel ® LP200 ComparisonK3 PVA 26-88* Comprecel ® M302 *ground PVA

3b. Compression of these blends and tablet characterisation

Gen. description: 1.25 g of magnesium stearate are added to in each case498.75 g of the co-mixtures of Examples A3-C3 or Comparisons D3-K3prepared above in a Turbula mixing vessel, the mixture is mixed againfor 5 min. in a T2A Turbula mixer and tabletted in a Korsch EK 0-DMSeccentric press.

The comparison used is Parteck® M200 blended with 1% of Parteck® LUBMST. Note: compression of Parteck® M200 with less magnesium stearate isnot possible owing to the very high ejection forces which otherwiseresult.

TABLE 3b Tableting data of the co-mixtures of ground PVA 26-88 withmicrocrystalline celluloses A Nominal Actual B C D E F Example 5 5.1104.9 487.9 5.2 0.08 97.2 A3 10 9.0 190.6 481.6 4.8 0 102.7 20 17.3350.8 476.0 4.3 0 69.7 30 27.2 469.7 473.4 4.1 0 43.2 Example 5 4.9 93.5497.9 5.5 0.33 98.1 B3 10 10.6 221.4 500.0 4.8 0.09 99.3 20 20.5 408.6503.0 4.4 0.02 62.8 30 30.6 492.3 503.4 4.3 0.03 51.7 Example 5 4.7 79.9496.6 5.5 0.37 93.6 C3 10 10.5 201.5 500.1 4.8 0.05 93.4 20 19.6 348.8503.2 4.5 0 58.5 30 31.3 424.1 502.9 4.4 0 44.8 Comparison 5 4.9 70.2501.8 5.4 0.49 85.9 D3 10 9.6 153.1 506.1 4.9 0.16 87.3 20 18.4 267.3506.6 4.5 0.07 61.1 30 28.6 325.1 506.8 4.4 0.04 52.1 Comparison 5 5.150.4 495.5 5.4 1.18 80.1 E3 10 9.7 106.3 499.2 4.8 0.38 80.9 20 18.8180.1 499.6 4.5 0.21 60.3 30 30.2 209.6 499.7 4.4 0.16 55.4 Comparison 54.8 47.6 496.3 5.6 1.52 95.3 F3 10 10.2 134.0 501.1 4.9 0.16 105.2 2020.7 251.4 502.9 4.5 0.06 75.5 30 31.6 299.4 503.7 4.4 0.03 66.2Comparison 5 5.2 70.2 497.8 5.5 0.39 87.9 G 10 9.8 146.5 498.1 4.9 0.0892.4 20 19.8 273.1 499.8 4.5 0.01 66.2 30 30.8 331.8 499.9 4.4 0 56.8Comparison 5 5.1 76.8 498.4 5.4 0.26 91.3 G3 10 10.2 171.4 502.1 4.80.05 91.8 20 19.5 295.7 503.4 4.5 0 66.7 30 30.0 354.5 502.5 4.4 0 58.6Comparison 5 4.8 41.8 498.4 5.5 1.89 88.5 H3 10 9.8 113.0 502.7 4.9 0.2996.4 20 20.5 213.8 502.1 4.4 0.09 70.0 30 30.4 244.2 502.6 4.4 0.07 64.2Comparison 5 4.9 71.0 494.2 5.5 0.39 90.9 I3 10 10.2 159.6 497.0 4.90.06 92.3 20 20.0 273.6 496.8 4.5 0 64.8 30 30.4 318.0 498.2 4.4 0 57.3Comparison 5 5.1 28.6 494.9 5.5 5.64 93.4 J3 10 10.0 78.7 499.2 4.9 0.4697.3 20 20.3 144.7 501.0 4.5 0.15 70.7 30 29.6 161.2 501.9 4.4 0.12 63.9Comparison 5 5.1 39.8 497.6 5.5 1.50 90.4 K3 10 10.2 100.6 499.1 4.90.16 93.6 20 19.0 184.2 500.1 4.5 0.03 71.6 30 30.7 224.2 500.6 4.4 0.0262.3 Parteck ® 5 5.2 84.1 497.8 5.1 0.21 155.8 M200 10 10.7 196.5 500.64.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 396.7 498.3 4.00.16 647.6 Key: A: Pressing force [kN] B: Tablet hardness after 1 day[N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F:Ejection force (N)

FIG. 3 shows a graph of the very different pressing force/tablethardness profiles for better illustration.

4a. Preparation of the blends of the directly compressible excipientswith the ground PVA grade 40-88

General description: ground PVA 40-88 is passed through an 800 μm handsieve in order to remove any coarse components and agglomerates. 300 gof this sieved product are weighed out into a 2 l Turbula mixing vessel,300 g of the corresponding microcrystalline cellulose from Table 4a areadded and mixed for 5 min. in a T2A Turbula mixer.

TABLE 4a Composition of the co-mixtures of ground PVA 40-88 withmicrocrystalline celluloses Composition 50% by weight of PVA 50% byweight of MCC Example A4 PVA 40-88* Avicel ® PH 105 Example B4 PVA40-88* Vivapur ® 101 Example C4 PVA 40-88* Avicel ® PH 101 Comparison D4PVA 40-88* Vivapur ® 12 Comparison E4 PVA 40-88* Vivapur ® 102 PremiumComparison F4 PVA 40-88* Vivapur ® 200 Comparison G4 PVA 40-88*Emcocel ® LP200 *ground PVA

4b. Compression of these blends and tablet characterisation

Gen. description: 1.25 g of magnesium stearate are added to in each case498.75 g of the co-mixtures of Examples A4-C4 or Comparisons D4-G4prepared above in a Turbula mixing vessel, the mixture is mixed againfor 5 min. in a T2A Turbula mixer and tabletted in a Korsch EK 0-DMSeccentric press.

The comparison used is Parteck® M200 blended with 1% of Parteck® LUBMST. Note: compression of Parteck® M200 with less magnesium stearate isnot possible owing to the very high ejection forces which otherwiseresult.

TABLE 4B Tableting data of the co-mixtures of ground PVA 40-88 withmicrocrystalline celluloses A Nominal Actual B C D E F Example A4 5 5.4110.8 488.7 5.3 0.11 100.3 10 10.4 235.6 488.4 4.7 0 97.4 20 23.1 462.7481.9 4.3 0 53.0 30 29.5 546.4 485.6 4.2 0 44.2 Example B4 5 5.1 88.3495.9 5.3 0.41 82.9 10 10.6 203.5 496.2 4.7 0.13 81.8 20 19.7 352.1501.1 4.4 0.06 56.7 30 28.8 414.9 504.0 4.4 0.07 47.5 Example C4 5 5.174.2 499.8 5.5 0.57 85.9 10 9.6 152.8 501.6 5.0 0.19 87.9 20 19.4 289.0503.2 4.5 0.06 58.1 30 29.7 358.2 503.8 4.4 0.07 47.5 Comparison 5 5.035.7 497.3 5.5 2.89 81.7 D4 10 10.0 87.3 502.0 4.9 0.32 91.4 20 20.7172.5 502.4 4.5 0.11 67.6 30 30.3 205.5 504.9 4.4 0.05 59.4 Comparison 55.0 64.2 500.4 5.4 0.49 86.8 E4 10 10.3 146.9 505.7 4.9 0.15 87.3 2020.1 247.4 506.0 4.5 0.08 62.5 30 32.0 296.6 506.0 4.5 0.07 55.9Comparison 5 5.2 32.9 497.1 5.5 3.16 72.9 F4 10 10.4 82.3 500.8 4.8 0.4379.2 20 19.6 149.2 501.2 4.4 0.18 60.9 30 30.9 180.2 502.7 4.4 0.12 54.8Comparison 5 5.2 19.4 491.0 5.5 100.0 75.3 G4 10 10.0 45.7 498.5 5.01.26 80.0 20 20.2 92.7 500.4 4.6 0.33 59.3 30 31.0 105.9 501.9 4.5 0.2652.6 Parteck ® 5 5.2 84.1 497.8 5.1 0.21 155.8 M200 10 10.7 196.5 500.64.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 30.0 396.7 498.34.0 0.16 647.6 Key: A: Pressing force [kN] B: Tablet hardness after 1day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F:Ejection force (N)

FIG. 4 shows a graph of the very different pressing force/tablethardness profiles for better illustration.

1-14. (canceled)
 15. A method for the production of tablets, wheretablets having hardnesses of ≥153 N with a friability of ≤0.2% by weightare obtained by compression with a pressing force of 10 kN, comprisingpreparing said tablets from directly compressible co-mixtures comprisingfine-grained polyvinyl alcohols (PVAs) and fine-grained microcrystallinecelluloses (MCCs).
 16. A method for the production of tablets, wheretablets having hardnesses of ≥289 N with a friability of ≤0.1% by weightare obtained by compression with a pressing force of 20 kN, comprisingpreparing said tablets from directly compressible co-mixtures comprisingfine-grained polyvinyl alcohols (PVAs) and fine-grained microcrystallinecelluloses (MCCs).
 17. The method for the production of tabletsaccording to claim 15, wherein the fine-grained polyvinyl alcohols(PVAs) are in the form of water-soluble, synthetic resins of thefollowing formula(C₂H₄O)_(n)  in which  n denotes an integer of 500 to 5000, and havebeen obtained by 85-89% hydrolysis of polyvinyl acetate, and have anaverage particle size D_(v50) of 50 to 260 μm, in any of the followingmeasuring methods: laser diffraction with dry dispersal (1 barcounterpressure), laser diffraction with dry dispersal (2 barcounterpressure), laser diffraction with dry dispersal (3 barcounterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil), and fine-grained microcrystallinecelluloses (MCCs), have an average particle size of D_(v50)<100 μm, inany of the following measuring methods: laser diffraction with drydispersal (1 bar counterpressure), laser diffraction with dry dispersal(2 bar counterpressure), laser diffraction with dry dispersal (3 barcounterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil).
 18. The method for the production oftablets according to claim 15, wherein the polyvinyl alcohol has beenground to give a fine-grained powder having an average particle sizeD_(v50) of 50 to 260 μm, a bulk density of 0.55 to 0.62 g/ml and anangle of repose of 35 to 38° and has been sieved through an 800 μmsieve.
 19. The method for the production of tablets according to claim15, wherein the fine-grained microcrystalline celluloses have an averageparticle sizes of D_(v50)<100 μm in any of the following measuringmethods: laser diffraction with dry dispersal (1 bar counterpressure),laser diffraction with dry dispersal (2 bar counterpressure), laserdiffraction with dry dispersal (3 bar counterpressure) or laserdiffraction with wet dispersal (in low-viscosity silicone oil).
 20. Themethod for the production of tablets according to claim 16, wherein thefine-grained polyvinyl alcohols (PVAs) are in the form of water-soluble,synthetic resins of the following formula(C₂H₄O)_(n)  in which  n denotes an integer of 500 to 5000, and havebeen obtained by 85-89% hydrolysis of polyvinyl acetate, and have anaverage particle size D_(v50) of 50 to 260 μm, in any of the followingmeasuring methods: laser diffraction with dry dispersal (1 barcounterpressure), laser diffraction with dry dispersal (2 barcounterpressure), laser diffraction with dry dispersal (3 barcounterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil), and fine-grained microcrystallinecelluloses (MCCs), have an average particle size of D_(v50)<100 μm, inany of the following measuring methods: laser diffraction with drydispersal (1 bar counterpressure), laser diffraction with dry dispersal(2 bar counterpressure), laser diffraction with dry dispersal (3 barcounterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil).
 21. The method for the production oftablets according to claim 16, wherein the polyvinyl alcohol has beenground to give a fine-grained powder having an average particle sizeD_(v50) of 50 to 260 μm, a bulk density of 0.55 to 0.62 g/ml and anangle of repose of 35 to 38° and has been sieved through an 800 μmsieve.
 22. The method for the production of tablets according to claim16, wherein the fine-grained microcrystalline celluloses have an averageparticle sizes of D_(v50)<100 μm in any of the following measuringmethods: laser diffraction with dry dispersal (1 bar counterpressure),laser diffraction with dry dispersal (2 bar counterpressure), laserdiffraction with dry dispersal (3 bar counterpressure) or laserdiffraction with wet dispersal (in low-viscosity silicone oil).
 23. Anactive compound-containing tablet having extended release of activecompound, comprising fine-grained polyvinyl alcohols (PVAs) andfine-grained microcrystalline celluloses (MCCs), wherein the polyvinylalcohol has been ground to give a fine-grained powder having an averageparticle size D_(v50) of 50 to 260 μm, a bulk density of 0.55 to 0.62g/ml and an angle of repose of 35 to 38° and has been sieved through an800 μm sieve, and wherein the active compound has a homogeneousdistribution in the tablet.
 24. The active compound-containing tabletaccording to claim 23 having extended release of active compound ofseveral hours, comprising a co-mixture of fine-grained polyvinylalcohols (PVAs) and fine-grained microcrystalline celluloses (MCCs). 25.The active compound-containing tablet according to claim 23, comprisinga directly compressible co-mixture comprising PVAs and MCCs in an amountin the range 1-99% by weight based on the total weight of the tablet.26. The active compound-containing tablet according to claim 23, which,in the case of production using low pressing forces, give tablets havinga hardness of up to 462 N and low friabilities of ≤0.2% by weight, butwhere only low ejection forces have to be used.
 27. The activecompound-containing tablet according to claim 23, having delayed releaseof active compound, comprising one or more active compounds in BCS classI, either alone or in combination with other active compounds.
 28. Theactive compound-containing tablet according to claim 23, comprisingfine-grained polyvinyl alcohols to fine-grained microcrystallinecelluloses in a ratio of 5:1 to 1:5 based on weight.
 29. The activecompound-containing tablet according to claim 23, comprisingfine-grained polyvinyl alcohols which meet the requirements of thepharmacopoeias (Ph. Eur., USP and JPE) and which are suitable forretardation of active compound; or fine-grained polyvinyl alcohols ofgrades 4-88, 18-88, 26-88 and 40-88, which meet the requirements of thepharmacopoeias Ph. Eur., JPE and USP, and grade 28-99, which meet therequirements of the pharmacopoeia pharmacopoeias JPE and Ph. Eur. 30.The active compound-containing tablet according to claim 23, comprisingfine-grained polyvinyl alcohols (PVAs) which meet the requirements ofthe pharmacopoeia Ph. Eur. and which have been obtained bypolymerisation of vinyl acetate and by subsequent partial of virtuallycomplete hydrolysis of the polyvinyl acetate and have an averagerelative molecular weight in the range between 20,000 and 150,000 g/mol,and which have a viscosity, in accordance with Ph. Eur., in the range3-70 mPa·s, (measured in a 4% solution at 20° C.) and have an estervalue of not greater than 280 mg of KOH/g (degree of hydrolysis >72.2mol %).
 31. The active compound-containing tablet according to claim 23,comprising fine-grained polyvinyl alcohols (PVAs) which meet therequirements of the pharmacopoeia USP and are in the form ofwater-soluble, synthetic resins which are characterised by the formula(C₂H₄O)_(n) in which n denotes an integer in the range of 500 to 5000,and which have been obtained by 85-89% hydrolysis of the polyvinylacetate.
 32. The active compound-containing tablet according to claim23, comprising fine-grained polyvinyl alcohols (PVAs), which are in theform of water-soluble, synthetic resins of the following formula(C₂H₄O)_(n)  in which  n denotes an integer of 500 to 5000, and havebeen obtained by 85-89% hydrolysis of polyvinyl acetate, and have anaverage particle size D_(v50) of 50 to 260 μm, in any of the followingmeasuring methods: laser diffraction with dry dispersal (1 barcounterpressure), laser diffraction with dry dispersal (2 barcounterpressure), laser diffraction with dry dispersal (3 barcounterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil), and fine-grained microcrystallinecelluloses (MCCs), which have an average particle size of D_(v50)<100μm, in any of the following measuring methods: laser diffraction withdry dispersal (1 bar counterpressure), laser diffraction with drydispersal (2 bar counterpressure), laser diffraction with dry dispersal(3 bar counterpressure) or laser diffraction with wet dispersal (inlow-viscosity silicone oil).
 33. The active compound-containing tabletaccording to claim 23, which contains at least about 50% by weight offine-grained polyvinyl alcohols (PVAs).
 34. The activecompound-containing tablet according to claim 23, which is an uncoatedtablet.